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Blood, 15 July 2007, Vol. 110, No. 2, pp. 536-543.
Prepublished online as a Blood First Edition Paper on March 15, 2007; DOI 10.1182/blood-2007-01-068395.
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Submitted January 17, 2007
Accepted March 10, 2007
Osteoprotegerin increases leukocyte adhesion to endothelial cells both in vitro and in vivo
Giorgio Zauli*, Federica Corallini, Fleur Bossi, Fabio Fischetti, Paolo Durigutto, Claudio Celeghini, Francesco Tedesco, and Paola Secchiero
Department of Biomedicine, University of Trieste, Trieste, Italy
Department of Physiology and Pathology, University of Trieste, Trieste, Italy
Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy
* Corresponding author; email: zauli{at}units.it.
Recombinant osteoprotegerin (OPG) promoted the adhesion of both primary polymorphonuclear neutrophils (PMN) and leukemic HL60 cells to endothelial cells. Leukocyte/endothelial cell adhesion was promoted by short (peak at 1 hour) pre-incubation of either endothelial cells or PMN with OPG, and the peak of pro-adhesive activity was observed in the same range of OPG concentrations detected in the sera of patients affected by cardiovascular diseases. While membrane RANKL and TRAIL, the cognate high-affinity ligands for OPG, were detected at significant levels on both PMN and HL60, they were not expressed on the surface of endothelial cells. However, pre-incubation of OPG with heparin abrogated its pro-adhesive activity, while pretreatment of endothelial cells with chondroitinase plus heparinases significantly decreased the pro-adhesive activity of OPG. Taken together, these findings suggest the involvement of both the ligand binding and the N-terminal heparin-binding domains of OPG in mediating its pro-adhesive activity. The relevance of these in vitro findings was underscored by in vivo experiments, in which the topical administration of recombinant OPG increased leukocyte rolling and adhesion to rat mesenteric post-capillary venules. Our data suggest that a pathological increase of OPG serum levels might play an important role in promoting leukocyte/endothelial cell adhesion.

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